More than 100 million Americans are obese and 17 million are affected by type 2 diabetes. While diet and lack of physical exercise are the main risk factors for these diseases, several epidemiological and animal studies have shown that the intrauterine nutritional conditions can also influence body weight and glucose homeostasis in adulthood. We hypothesize that maternal nutrition influences the intrauterine environment and can induce genome-wide DNA methylation changes in multiple organs of the fetus. We hypothesize that this epigenetic programming is responsible for translating intrauterine stress into molecular responses that can durably affect the health of the offspring. We propose to test this hypothesis by studying a mouse model of diet-induced maternal obesity using a unique combination of high-throughput genomic tools: the characterization of the genome-wide DNA methylation patterns, using a novel sequencing developed in our lab, and extensive gene expression profiling in multiple tissues. We will study embryos and newborns from C57BL6 dams fed on high- fat or low-fat diet prior and during pregnancy to characterize the molecular basis of intrauterine programming. We will also analyze older animals to understand the lasting molecular and phenotypic consequences of maternal obesity. Our findings will provide a better understanding of the mechanisms responsible for the life-long metabolic consequences of maternal obesity, which currently affects 20-40% of pregnant women in the US. PUBLIC HEALTH RELEVANCE: Maternal obesity currently affects 20-40% of pregnant women in the United States and is a growing public health concern since the offspring of obese mother tend to develop obesity and type 2 diabetes in adulthood. We propose to study the molecular consequences of maternal obesity using a mouse model of diet-induced obesity and state-of-the-art genomic methods. Our findings will provide a better understanding of the biological mechanisms underlying the translation of intrauterine stress into life-long health consequences.